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Metabolic control of dendritic cell activation and function: recent advances and clinical implications

Metabolic control of dendritic cell activation and function: recent advances and clinical... MINI REVIEW ARTICLE published: 08 May 2014 doi: 10.3389/fimmu.2014.00203 Metabolic control of dendritic cell activation and function: recent advances and clinical implications 1,2 1 Bart Everts and Edward J. Pearce * Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands Edited by: Dendritic cells (DCs) are key regulators of both immunity and tolerance by controlling acti- Marianne Boes, University Medical vation and polarization of effector T helper cell and regulatory T cell responses. Therefore, Centre Utrecht, Netherlands there is a major focus on developing approaches to manipulate DC function for immunother- Reviewed by: apy. It is well known that changes in cellular activation are coupled to profound changes Amir Ghaemmaghami, The University of Nottingham, UK in cellular metabolism. Over the past decade there is a growing appreciation that these Curdin Conrad, Centre Hospitalier metabolic changes also underlie the capacity of immune cells to perform particular func- Universitaire Vaudois, Switzerland tions. This has led to the concept that the manipulation of cellular metabolism can be used *Correspondence: to shape innate and adaptive immune responses. While most of our understanding in this Edward J. Pearce, Department of area has been gained from studies with T cells and macrophages, evidence is emerging Pathology and Immunology, that the activation and function of DCs are also dictated by the type of metabolism these Washington University School of Medicine, Campus Box 8118, 660 S. cells commit to. We here discuss these new insights and explore whether targeting of Euclid Avenue, St. Louis, MO 63110, metabolic pathways in DCs could hold promise as a novel approach to manipulate the USA functional properties of DCs for clinical purposes. e-mail: edwardpearce@path. wustl.edu Keywords: metabolism, oxidative phosphorylation, mitochondria, glycolysis,TLR signaling, immunogenic dendritic cells, tolerogenic dendritic cells, immunotherapy INTRODUCTION processes also control the activation and immune-priming func- Dendritic cells (DCs) play a crucial role in the development of tions of DCs. In the current review, we will discuss these recent adaptive immune responses during infections and inflammatory findings and explore whether targeting of metabolic pathways in diseases, as well as in the regulation of immune homeostasis dur- DCs could hold promise as a novel approach to manipulate their ing steady state, by governing the activation and maintenance of functional properties for DC-based immunotherapy. T cell responses. In response to many viral and bacterial infec- tions, DCs promote the generation of effector CD4 T helper 1 ROLE OF CELLULAR METABOLISM IN DC FUNCTION (Th1) and CD8 T cell-dominated immune responses, while fun- Under non-inflammatory conditions, most DCs reside in periph- gal and parasitic worm infections are predominantly associated eral tissues where they exist in a resting immature state. In this with Th17 and Th2 responses, respectively. In addition to these quiescent state, DCs are poorly immunogenic. However, upon trig- effector responses, DCs can be instructed to become tolerogenic gering of a set of germline-encoded pattern recognition receptors, and promote regulatory T cells (Tregs), which regulate effector T including Toll-like receptors (TLRs) by pathogen-derived prod- cell responses, a process that is crucial for maintenance of immune ucts or inflammatory stimuli, DCs undergo a well-characterized homeostasis and control of autoimmune disorders and allergies. process of cellular activation, termed DC maturation, which ren- Because of the powerful immunoregulatory functions of DCs, ders them highly immunogenic. This process involves an increase there has been great interest in delineating the cellular processes in capturing and processing of antigens for antigen presentation that control the different properties of these cells, to ultimately in context of major histocompatibility complex I (MHC-I) and identify ways to manipulate the function of DCs for the rational MHC-II and the induction of expression of chemokine recep- design of DC-based immune-interventions. tors, pro-inflammatory cytokines, and costimulatory molecules. It has long been appreciated, especially in the cancer field, that This activation program endows DCs with the capacity to traf- changes in cellular activation coincide with, and are underpinned fic, via tissue-draining lymphatics, to T cell zones of secondary by, alterations in cellular metabolic state (1, 2). Importantly, over lymphoid organs to efficiently prime and control effector T cell the last couple of years it is becoming increasingly clear that responses (9). immune cell activation is also coupled to profound changes in cel- In T cells, catabolic metabolism centered around mitochondrial lular metabolism and that their fate and function are metabolically oxidative phosphorylation (OXPHOS) is associated with cellular regulated (3). This has led to the idea that manipulation of cellu- longevity and quiescence, whereas cellular activation and prolif- lar metabolism of immune cells can be used to shape innate and eration are accompanied by a switch to glycolytic metabolism to adaptive immune responses to our advantage. While most of our support anabolic pathways needed for biosynthesis (4–6). Consis- understanding in this area has been gained from studies with T cells tent with these observations, DCs when activated by TLR agonists, (4–6) and macrophages (7, 8), evidence is emerging that metabolic undergo a robust metabolic switch characterized by an increase www.frontiersin.org May 2014 | Volume 5 | Article 203 | 1 Everts and Pearce Metabolic control of DC function in glycolysis and a concomitant progressive loss of OXPHOS (10– DCs to meet the bioenergetic and anabolic needs of TLR-driven 13). We have shown that in inflammatory DC subsets, such as DC activation itself. Indeed, we observed that TLR stimulation murine GM-CSF-derived bone marrow DCs (14), this switch from in both cDCs and inflammatory DCs results within minutes in OXPHOS to glycolysis is a direct consequence of TLR-induced an increase in glycolytic rate that is maintained for several hours inducible nitric oxide synthase (iNOS) expression that through the after which it returns to prestimulation levels in the absence of production of nitric oxide (NO) poisons the mitochondrial res- iNOS (16). Inhibition of this early metabolic reprograming blunts piratory chain in an autocrine fashion (15). In this setting, in the DC activation, migration, and T cell priming both in vitro and absence of functional OXPHOS, TLR-agonist activated inflamma- in vivo, illustrating its importance for DC biology. Functionally, tory DCs depend heavily on glycolysis as their sole source of ATP as opposed to the long-term glycolytic commitment, the rapid for survival both in vitro and in vivo (12). Consistent with this, increase in glycolysis appears not to be important as a rapid source in vitro and ex vivo TLR-activated Nos2 inflammatory DCs of ATP, but rather to serve a central anabolic role by acting as still have functional OXPHOS and as result do not display a long- a carbon source for both the pentose phosphate pathway (PPP) term increase in glycolytic metabolism (12). Likewise, we did not and the tricarboxylic (TCA) cycle to support the generation of observe a switch to glycolytic metabolism following TLR stimula- NADPH and citrate, respectively, that are used for de novo fatty tion of conventional DCs (cDCs) ex vivo (12), which do not express acid (FA) synthesis. Moreover, glycolysis-supported de novo FA iNOS in response to TLR stimulation. However, a more recent synthesis plays a crucial role in DC activation and function at in vivo study showed that TLR-activated cDCs do display long- the posttranscriptional level, by allowing for the synthesis and term diminished mitochondrial activity and enhanced glycolysis expansion of membranes including Golgi and ER that are required (13). They found that this metabolic shift is iNOS-independent for synthesis, transport, and secretion of proteins associated with and instead driven by TLR-induced autocrine type I interferon TLR-driven DC activation (16). These findings share strong paral- production. Despite the differences in mechanism underlying the lels with activated T cells that heavily rely on glycolysis as a carbon metabolic switch, similar to inflammatory DCs, cDCs seem to rely source for de novo FA synthesis to support the need for mem- on the glycolytic shift for ATP production for their survival (13) brane synthesis required for cellular proliferation (17). However, (Figure 1). in contrast to T cells, DCs do not proliferate and seem to use this These studies suggest that the metabolic reprograming toward pathway to expand the cellular machinery necessary for increased glycolytic metabolism is a consequence of TLR-driven DC acti- production and secretion of the mediators that are integral to DC vation, rather than a prerequisite for it. However, given the fact activation (Figure 1). This is consistent with a recent study posi- that TLR stimulation results in a rapid activation program in both tively correlating lipid content with immunogenicity of DCs in the cDCs and inflammatory DCs, we recently tested the hypothesis liver and showing that the immunogenicity of DCs with high lipid that rapid metabolic reprograming needs to occur in both types of content is dependent on FA synthesis (18). Taken together, these FIGURE 1 |TLR-induced metabolic changes in dendritic cells. maturation. (B) Following activation, DCs sustain high glycolytic rates to (A) Rapid induction of glycolysis in DCs by TLR stimulation serves an generate ATP to compensate for the loss of mitochondrial function. In anabolic role in DC activation, by generating lipids for synthesis of cDCs this process appears to be driven by autocrine type I interferon, additional membranes including ER and Golgi to support the increased while in inflammatory DCs this is a direct consequence of iNOS-derived demands of synthesis and transport of proteins required for DC NO that blocks OXPHOS. Frontiers in Immunology | Antigen Presenting Cell Biology May 2014 | Volume 5 | Article 203 | 2 Everts and Pearce Metabolic control of DC function studies illustrate that the induction of glycolysis plays a central DCs and cDCs in response to TLR stimulation (11, 13). More- role for DCs to acquire immunogenic properties as well as their over, consistent with its well-recognized role in regulating innate survival following activation. immune cell function under inflammatory conditions (42), TLR- While the metabolic features of immunogenic DCs are becom- induced DC activation and T cell priming appear to rely on HIF-1a ing more well characterized, there is still little known about the (11, 13, 43). However, whether this is a consequence of the role metabolism of tolerogenic DCs. Tolerogenic DCs, as opposed to of HIF-1a in promoting glycolytic metabolism and thereby cell immunogenic DCs, are generally characterized by the absence survival, or a reflection of the direct control of expression of of traditional signs of activation, are maturation-resistant, and inflammatory cytokines independently from glycolytic regulation express increased levels of immunoregulatory factors, impor- (44, 45), remains to be addressed. In addition to direct tran- tant for controlling Treg responses (19–21). Consistent with this scriptional regulation of glycolysis through HIF-1a, mTOR may immature, maturation-resistant phenotype, proteomic analysis of regulate the TLR-induced commitment to glycolysis indirectly in human DCs treated with dexamethasone and vitamin-D3, two inflammatory DCs, through induction of iNOS expression and well known immunosuppressive drugs that induce tolerogenic NO production (46, 47) that forces these cells to switch to glycolysis DCs, revealed increased expression of genes associated with mito- in the absence of mitochondrial respiration (12). chondrial metabolism and OXPHOS (22, 23). Furthermore, DCs In contrast to the clear role for the mTOR-HIF-1a axis in regu- conditioned by IL-4 acquire a phenotype highly reminiscent of lating TLR-induced long-term metabolic changes, recent evidence alternatively activated (M2) macrophages and expression of M2- suggests that the early TLR-driven induction of glycolysis to sup- associated activation markers on DCs is required for optimal port the anabolic demands of DC activation itself does not depend induction of IL-10-secreting T cells (24). The fact that M2 activa- on mTOR or HIF-1a signaling (16, 48). Instead, there is a critical tion by IL-4 is dependent on increased fatty acid oxidation (FAO) role for Akt in this response that directly enhances the enzymatic and OXPHOS (25–27) makes it conceivable that there is a causal activity of rate-limiting glycolytic enzyme hexokinase-II (HK-II) link between mitochondrial metabolism fueled by FAO and the by promoting its association with the mitochondria. Interestingly, acquisition of a tolerogenic phenotype by DCs. The observations Tank-Binding Kinase 1 (TBK1) and IkB kinase-(IKK) but not the that direct inhibition of glycolysis in TLR-activated DCs favors the canonical Akt activators PI3K or mTORC2 appear to be the cru- induction of Foxp3-expressing Th cells at the expense of IFN-g- cial upstream regulators of Akt activation in this TLR-driven rapid producing Th1 cells (16), and that resveratrol and rosiglitazone, induction of glycolysis (16). Taken together based on these recent drugs known to promote FAO (28) and mitochondrial biogen- findings a picture is emerging that TLR-signaling drives two func- esis (29), respectively, interfere with TLR-induced DC activation tionally and temporally distinct waves in glycolytic metabolism and can render them tolerogenic (30–33), would support this idea. in DCs that are controlled by largely separate signaling pathways However, these studies are mostly correlative and more work will (Figure 1). be needed to elucidate whether there is a direct functional link While the signaling pathways that promote the shift to glycoly- between mitochondrial catabolic metabolism and the acquisition sis and anabolic metabolism required for TLR-induced activation of tolerogenic properties of DCs. and immunogenicity of DCs are starting to be characterized, much less is known about the signals in DCs that may antag- REGULATORS OF DC METABOLISM onize these responses and that are potentially important for In recent years, major advances have been made in unraveling induction and function of tolerogenic DCs. In this respect, in the signaling pathways in immune cells that regulate their meta- T cells and in macrophages the metabolic sensor AMP Kinase bolic state. The conserved kinase mammalian/mechanistic target (AMPK) is known to play a central role in antagonizing biosyn- of rapamycin (mTOR) and its upstream activators PI3K-Akt have thetic pathways, including lipogenesis, and has instead been shown been identified as central regulators of cellular activation and pro- to promote catabolic metabolism by, amongst other pathways, the liferation due to their ability to control glycolysis and anabolic activation of peroxisome proliferator-activated receptor gamma metabolism (34–36). Consistent with a role for mTOR in regulat- coactivator (PGC)-1a that promotes mitochondrial biogenesis to ing DC metabolism as well, cDCs isolated from mice with a DC- increase mitochondrial OXPHOS (7, 35). Consistent with these specific deletion of tuberous sclerosis 1 (Tsc1), a negative regulator observations, pharmacological activation of AMPK suppresses of mTOR, display enhanced mTOR activity, an increase of expres- TLR-induced glucose consumption and activation of DCs, while sion of glycolytic and lipogenic genes, and of maturation markers knockdown of AMPK has the opposite effect (10, 49), suggesting at steady state (37). Also in response to TLR ligands inflamma- an important role for AMPK signaling in the metabolic con- tory DCs depend on signaling through PI3K, Akt, and mTOR for trol of DC activation. Furthermore, systemic administration of their long-term commitment to glycolysis (10, 38). mTOR pro- drugs activating AMPK signaling to promote catabolic metabo- motes anabolic pathways and glycolysis by driving expression and lism drives induction of tolerogenic immune responses in several stabilization of transcription factors such as sterol-regulatory ele- inflammatory disease models (50–52). However, it remains to be ment binding protein (SREBP) (39, 40) and hypoxia-inducible determined whether these treatments exert their effects through factor (HIF)-1a (41), that control expression of genes involved in direct induction of tolerogenic DCs. Moreover, resveratrol, a drug lipogenesis and glycolysis, respectively. While it remains unknown that has been linked to induction of tolerogenic DCs, is thought whether SREBP plays a role in DC metabolism, several studies have to favor catabolic metabolism through activation of the histone documented an important role for HIF-1a in supporting the long- deacetylase Sirtuin 1, which is known to suppress HIF-1a function term commitment in glycolytic metabolism of both inflammatory as well as enhance PGC-1a activity (29, 32, 53). In addition, www.frontiersin.org May 2014 | Volume 5 | Article 203 | 3 Everts and Pearce Metabolic control of DC function Based on the importance of anabolic metabolism and glycol- ysis in supporting DC activation and immunogenicity, and the possible role of catabolic metabolism in supporting tolerogenic DC function, it will be of great interest to assess whether promot- ing these types of metabolism in DCs can be used as a strategy to enhance the immunogenicity or tolerogenicity of DCs in therapeu- tic settings. It should be noted that some of the pharmacological approaches currently used to manipulate the immunogenicity of DCs, such as dexamethasone, Vitamin-D3, and rapamycin (63– 66) that are known for their capacity to induce tolerogenic DCs, have been described to influence DC metabolism (22, 23, 38). Thus it is possible that direct targeting of metabolism of DCs as a single treatment may not be superior to some other already existing manipulations that also affect metabolism. It is there- FIGURE 2 | Putative metabolic pathways and upstream regulators in tolerogenic versus immunogenic dendritic cells. In red examples are fore more conceivable that manipulation of metabolism of DCs depicted of pharmacological approaches currently tested or used in other for immunotherapy will be most effective when used in con- therapeutic settings, that could be used to manipulate DC metabolism. junction with existing approaches to complement and enhance their therapeutic efficacy. A second important advantage of direct enforcement of certain types of metabolism in DCs is that is DCs deficient for Nuclear factor-erythroid 2 p45-related factor- it may render them more resistant to environmental metabolic 2 (NRF2) or PPAR-g, downstream targets of PGC-1a, display manipulation. This is highly relevant since a key parameter that increased maturation and T cell priming capacity (31, 54, 55). determines the efficacy of immunotherapies is how long targeted Hence, these studies may point toward an important role for the DCs retain their phenotype following their functional manipu- AMPK-PGC-1a axis in promoting mitochondria-centered cata- lation. The microenvironment, which DCs become exposed to bolic metabolism in DCs, which may be crucial for the acquisition in situ, may lead to the loss of immunogenicity or tolerogenic- of a tolerogenic phenotype (Figure 2). However, how these signal- ity and would significantly affect the outcome of the therapy. For ing pathways are regulated under physiological conditions and to instance, the immunostimulatory capacity of DCs is often sup- what extent the effects of these factors on DC biology can be attrib- pressed in a tumor microenvironment (67). Given the important uted to direct regulation of DC metabolism are still unresolved role for cellular metabolism in regulating DC function, many of questions. the suppressive effects of tumors appear to be attributable to effects on DC metabolism. It has been shown that tumor-derived IL-10 MANIPULATING DC METABOLISM FOR THERAPEUTIC can suppress glycolysis in DCs through down regulation of gly- PURPOSES? colytic enzyme pyruvate kinase (68). Additionally, yet unidentified There is a great interest in the use of DCs as targets for immune- tumor-derived factors can promote aberrant lipid accumulation intervention and for vaccine strategies, because of their powerful in DCs, resulting in impaired T cell priming (69, 70). Moreover, immune stimulatory as well as regulatory functions (56). The immunogenic DCs are likely to be impaired in their function in use of highly immunogenic DCs can be used to promote robust a microenvironment where glucose will be scarce due to the high cellular and humoral immunity that is central for improving vacci- glycolytic rates of tumors themselves (71). Finally, caloric intake nation efficacy against a variety of infectious diseases and tumors, and mitochondrial activity are important determinants of organ- while the use of tolerogenic DCs will allow for induction of regula- ismal as well as cellular lifespan (72, 73). Therefore targeting DCs tory immune responses in settings where unwanted effector T cell metabolism can also be used to manipulate DC longevity to affect responses need to be controlled, such as to prevent rejection fol- their immunostimulatory potential. For example, mTOR inhibi- lowing transplantation. It is of pivotal importance to identify and tion has shown to increase the lifespan of TLR-activated DCs and characterize the regulatory processes underpinning these different enhance their capacity to induce protective tumor immunity (38). functions of DCs. It is becoming clear from the aforementioned Several agonist and antagonists of metabolic enzymes and studies that the activation and T cell-priming function of DCs is upstream signaling pathways that could be used to manipulate tightly regulated by their metabolic fate. What can we learn from DC metabolism have already been developed and tested for safety these new metabolic insights in DC biology and would there be and efficacy in other systems (58–60, 74) (Figure 2). In addition ways to use this knowledge in developing approaches to enhance to pharmacological approaches, genetic manipulation through DC-based immunotherapies? The idea of manipulating cellular introduction of small hairpin RNAs has shown to be a successful metabolism for therapeutic purposes is not a new concept. In fact, strategy to alter DC immunogenicity (75, 76) and could provide in the cancer field there is great interest in the use of pharmaco- a feasible alternative to target DC metabolism. In recent years, logicals that inhibit anabolic metabolism or glycolysis to reduce there has been a major focus on manipulating the immunos- tumor growth (57–60). Likewise, studies in T cells have provided timulatory properties ex vivo generated DCs for autologous DC a clear proof of principle that targeting of cellular metabolism can vaccination. Some of these vaccines have made it to the clinic (77) provide a viable means for improving the efficacy of vaccinations or are currently in clinical trials (78–80). In addition, widespread (61, 62). enthusiasm has been generated by results from the in vivo use of Frontiers in Immunology | Antigen Presenting Cell Biology May 2014 | Volume 5 | Article 203 | 4 Everts and Pearce Metabolic control of DC function nanoparticles, consisting of antibody covered micelles carrying 13. Pantel A, Teixeira A, Haddad E, Wood EG, Steinman RM, Longhi MP. Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for antigens and potentially drugs or shRNA, that can be specifi- maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol cally targeted to DCs in situ (81, 82). Given the amenability of (2014) 12(1):e1001759. doi:10.1371/journal.pbio.1001759 cellular metabolic intervention, it seems feasible that metabolism- 14. Dominguez PM, Ardavin C. Differentiation and function of mouse monocyte- targeted manipulations to DCs could be implemented in protocols derived dendritic cells in steady state and inflammation. Immunol Rev (2010) for DC-based vaccinations. 234(1):90–104. doi:10.1111/j.0105- 2896.2009.00876.x 15. Cleeter MW, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AH. Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mito- CONCLUDING REMARKS chondrial respiratory chain, by nitric oxide. Implications for neurodegenerative It is becoming increasingly clear that the metabolic phenotype diseases. FEBS Lett (1994) 345(1):50–4. doi:10.1016/0014- 5793(94)00424- 2 of DCs dictates their activation and immunogenicity. However, 16. Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY, et al. TLR- driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon sup- many of the details and underlying mechanisms of how cellular ports the anabolic demands of dendritic cell activation. Nat Immunol (2014) metabolism controls the functional properties of DCs remain to 15(4):323–32. doi:10.1038/ni.2833 be determined. For instance, the precise metabolic processes that 17. Kidani Y, Elsaesser H, Hock MB, Vergnes L, Williams KJ, Argus JP, et al. Sterol reg- underpin the function of tolerogenic DCs are still poorly defined. ulatory element-binding proteins are essential for the metabolic programming Moreover, do different in vivo DC subsets have different meta- of effector T cells and adaptive immunity. Nat Immunol (2013) 14(5):489–99. doi:10.1038/ni.2570 bolic characteristics and are unique metabolic processes required 18. Ibrahim J, Nguyen AH, Rehman A, Ochi A, Jamal M, Graffeo CS, et al. Dendritic for DCs to perform particular functions, such as cross presenta- cell populations with different concentrations of lipid regulate tolerance and tion or the induction of Th1/2/17 cell responses? Addressing these immunity in mouse and human liver. Gastroenterology (2012) 143(4):1061–72. and other questions will not only contribute to a better funda- doi:10.1053/j.gastro.2012.06.003 19. Pulendran B, Tang H, Manicassamy S. Programming dendritic cells to induce mental understanding of the biology of DCs, but will also aid in T(H)2 and tolerogenic responses. Nat Immunol (2010) 11(8):647–55. doi:10. the rational design of metabolism-based approaches to enhance 1038/ni.1894 the efficacy of DC-based immunotherapies. 20. Svajger U, Obermajer N, Jeras M. Novel findings in drug-induced dendritic cell tolerogenicity. Int Rev Immunol (2010) 29(6):574–607. doi:10.3109/08830185. ACKNOWLEDGMENTS 2010.522280 21. Maldonado RA, von Andrian UH. How tolerogenic dendritic cells induce regula- The work was supported by the National Institutes of Health grants tory T cells. Adv Immunol (2010) 108:111–65. doi:10.1016/B978- 0- 12- 380995- to Edward J. Pearce (AI53825, CA164062), and by a Veni grant from 7.00004- 5 Netherlands Organisation for Scientific Research to Bart Everts. 22. Ferreira GB, Kleijwegt FS, Waelkens E, Lage K, Nikolic T, Hansen DA, et al. 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Cytother- Conflict of Interest Statement: The authors declare that the research was conducted apy (2013) 15(6):740–9. doi:10.1016/j.jcyt.2013.02.005 in the absence of any commercial or financial relationships that could be construed 77. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. as a potential conflict of interest. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med (2010) 363(5):411–22. doi:10.1056/NEJMoa1001294 78. Bregy A, Wong TM, Shah AH, Goldberg JM, Komotar RJ. Active immunotherapy Received: 01 February 2014; paper pending published: 02 April 2014; accepted: 24 April using dendritic cells in the treatment of glioblastoma multiforme. Cancer Treat 2014; published online: 08 May 2014. Rev (2013) 39(8):891–907. doi:10.1016/j.ctrv.2013.05.007 Citation: Everts B and Pearce EJ (2014) Metabolic control of dendritic cell activation 79. Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) and function: recent advances and clinical implications. Front. Immunol. 5:203. doi: study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Dia- 10.3389/fimmu.2014.00203 betes Care (2011) 34(9):2026–32. doi:10.2337/dc11- 0472 This article was submitted to Antigen Presenting Cell Biology, a section of the journal 80. Hilkens CM, Isaacs JD. Tolerogenic dendritic cell therapy for rheumatoid arthri- Frontiers in Immunology. tis: where are we now? Clin Exp Immunol (2013) 172(2):148–57. doi:10.1111/ Copyright © 2014 Everts and Pearce . This is an open-access article distributed under cei.12038 the terms of the Creative Commons Attribution License (CC BY). The use, distribution 81. Unger WW, van Beelen AJ, Bruijns SC, Joshi M, Fehres CM, van Bloois L, or reproduction in other forums is permitted, provided the original author(s) or licensor et al. Glycan-modified liposomes boost CD4+ and CD8+ T-cell responses by are credited and that the original publication in this journal is cited, in accordance with targeting DC-SIGN on dendritic cells. J Control Release (2012) 160(1):88–95. accepted academic practice. No use, distribution or reproduction is permitted which doi:10.1016/j.jconrel.2012.02.007 does not comply with these terms. www.frontiersin.org May 2014 | Volume 5 | Article 203 | 7 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Frontiers in Immunology Unpaywall

Metabolic control of dendritic cell activation and function: recent advances and clinical implications

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MINI REVIEW ARTICLE published: 08 May 2014 doi: 10.3389/fimmu.2014.00203 Metabolic control of dendritic cell activation and function: recent advances and clinical implications 1,2 1 Bart Everts and Edward J. Pearce * Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands Edited by: Dendritic cells (DCs) are key regulators of both immunity and tolerance by controlling acti- Marianne Boes, University Medical vation and polarization of effector T helper cell and regulatory T cell responses. Therefore, Centre Utrecht, Netherlands there is a major focus on developing approaches to manipulate DC function for immunother- Reviewed by: apy. It is well known that changes in cellular activation are coupled to profound changes Amir Ghaemmaghami, The University of Nottingham, UK in cellular metabolism. Over the past decade there is a growing appreciation that these Curdin Conrad, Centre Hospitalier metabolic changes also underlie the capacity of immune cells to perform particular func- Universitaire Vaudois, Switzerland tions. This has led to the concept that the manipulation of cellular metabolism can be used *Correspondence: to shape innate and adaptive immune responses. While most of our understanding in this Edward J. Pearce, Department of area has been gained from studies with T cells and macrophages, evidence is emerging Pathology and Immunology, that the activation and function of DCs are also dictated by the type of metabolism these Washington University School of Medicine, Campus Box 8118, 660 S. cells commit to. We here discuss these new insights and explore whether targeting of Euclid Avenue, St. Louis, MO 63110, metabolic pathways in DCs could hold promise as a novel approach to manipulate the USA functional properties of DCs for clinical purposes. e-mail: edwardpearce@path. wustl.edu Keywords: metabolism, oxidative phosphorylation, mitochondria, glycolysis,TLR signaling, immunogenic dendritic cells, tolerogenic dendritic cells, immunotherapy INTRODUCTION processes also control the activation and immune-priming func- Dendritic cells (DCs) play a crucial role in the development of tions of DCs. In the current review, we will discuss these recent adaptive immune responses during infections and inflammatory findings and explore whether targeting of metabolic pathways in diseases, as well as in the regulation of immune homeostasis dur- DCs could hold promise as a novel approach to manipulate their ing steady state, by governing the activation and maintenance of functional properties for DC-based immunotherapy. T cell responses. In response to many viral and bacterial infec- tions, DCs promote the generation of effector CD4 T helper 1 ROLE OF CELLULAR METABOLISM IN DC FUNCTION (Th1) and CD8 T cell-dominated immune responses, while fun- Under non-inflammatory conditions, most DCs reside in periph- gal and parasitic worm infections are predominantly associated eral tissues where they exist in a resting immature state. In this with Th17 and Th2 responses, respectively. In addition to these quiescent state, DCs are poorly immunogenic. However, upon trig- effector responses, DCs can be instructed to become tolerogenic gering of a set of germline-encoded pattern recognition receptors, and promote regulatory T cells (Tregs), which regulate effector T including Toll-like receptors (TLRs) by pathogen-derived prod- cell responses, a process that is crucial for maintenance of immune ucts or inflammatory stimuli, DCs undergo a well-characterized homeostasis and control of autoimmune disorders and allergies. process of cellular activation, termed DC maturation, which ren- Because of the powerful immunoregulatory functions of DCs, ders them highly immunogenic. This process involves an increase there has been great interest in delineating the cellular processes in capturing and processing of antigens for antigen presentation that control the different properties of these cells, to ultimately in context of major histocompatibility complex I (MHC-I) and identify ways to manipulate the function of DCs for the rational MHC-II and the induction of expression of chemokine recep- design of DC-based immune-interventions. tors, pro-inflammatory cytokines, and costimulatory molecules. It has long been appreciated, especially in the cancer field, that This activation program endows DCs with the capacity to traf- changes in cellular activation coincide with, and are underpinned fic, via tissue-draining lymphatics, to T cell zones of secondary by, alterations in cellular metabolic state (1, 2). Importantly, over lymphoid organs to efficiently prime and control effector T cell the last couple of years it is becoming increasingly clear that responses (9). immune cell activation is also coupled to profound changes in cel- In T cells, catabolic metabolism centered around mitochondrial lular metabolism and that their fate and function are metabolically oxidative phosphorylation (OXPHOS) is associated with cellular regulated (3). This has led to the idea that manipulation of cellu- longevity and quiescence, whereas cellular activation and prolif- lar metabolism of immune cells can be used to shape innate and eration are accompanied by a switch to glycolytic metabolism to adaptive immune responses to our advantage. While most of our support anabolic pathways needed for biosynthesis (4–6). Consis- understanding in this area has been gained from studies with T cells tent with these observations, DCs when activated by TLR agonists, (4–6) and macrophages (7, 8), evidence is emerging that metabolic undergo a robust metabolic switch characterized by an increase www.frontiersin.org May 2014 | Volume 5 | Article 203 | 1 Everts and Pearce Metabolic control of DC function in glycolysis and a concomitant progressive loss of OXPHOS (10– DCs to meet the bioenergetic and anabolic needs of TLR-driven 13). We have shown that in inflammatory DC subsets, such as DC activation itself. Indeed, we observed that TLR stimulation murine GM-CSF-derived bone marrow DCs (14), this switch from in both cDCs and inflammatory DCs results within minutes in OXPHOS to glycolysis is a direct consequence of TLR-induced an increase in glycolytic rate that is maintained for several hours inducible nitric oxide synthase (iNOS) expression that through the after which it returns to prestimulation levels in the absence of production of nitric oxide (NO) poisons the mitochondrial res- iNOS (16). Inhibition of this early metabolic reprograming blunts piratory chain in an autocrine fashion (15). In this setting, in the DC activation, migration, and T cell priming both in vitro and absence of functional OXPHOS, TLR-agonist activated inflamma- in vivo, illustrating its importance for DC biology. Functionally, tory DCs depend heavily on glycolysis as their sole source of ATP as opposed to the long-term glycolytic commitment, the rapid for survival both in vitro and in vivo (12). Consistent with this, increase in glycolysis appears not to be important as a rapid source in vitro and ex vivo TLR-activated Nos2 inflammatory DCs of ATP, but rather to serve a central anabolic role by acting as still have functional OXPHOS and as result do not display a long- a carbon source for both the pentose phosphate pathway (PPP) term increase in glycolytic metabolism (12). Likewise, we did not and the tricarboxylic (TCA) cycle to support the generation of observe a switch to glycolytic metabolism following TLR stimula- NADPH and citrate, respectively, that are used for de novo fatty tion of conventional DCs (cDCs) ex vivo (12), which do not express acid (FA) synthesis. Moreover, glycolysis-supported de novo FA iNOS in response to TLR stimulation. However, a more recent synthesis plays a crucial role in DC activation and function at in vivo study showed that TLR-activated cDCs do display long- the posttranscriptional level, by allowing for the synthesis and term diminished mitochondrial activity and enhanced glycolysis expansion of membranes including Golgi and ER that are required (13). They found that this metabolic shift is iNOS-independent for synthesis, transport, and secretion of proteins associated with and instead driven by TLR-induced autocrine type I interferon TLR-driven DC activation (16). These findings share strong paral- production. Despite the differences in mechanism underlying the lels with activated T cells that heavily rely on glycolysis as a carbon metabolic switch, similar to inflammatory DCs, cDCs seem to rely source for de novo FA synthesis to support the need for mem- on the glycolytic shift for ATP production for their survival (13) brane synthesis required for cellular proliferation (17). However, (Figure 1). in contrast to T cells, DCs do not proliferate and seem to use this These studies suggest that the metabolic reprograming toward pathway to expand the cellular machinery necessary for increased glycolytic metabolism is a consequence of TLR-driven DC acti- production and secretion of the mediators that are integral to DC vation, rather than a prerequisite for it. However, given the fact activation (Figure 1). This is consistent with a recent study posi- that TLR stimulation results in a rapid activation program in both tively correlating lipid content with immunogenicity of DCs in the cDCs and inflammatory DCs, we recently tested the hypothesis liver and showing that the immunogenicity of DCs with high lipid that rapid metabolic reprograming needs to occur in both types of content is dependent on FA synthesis (18). Taken together, these FIGURE 1 |TLR-induced metabolic changes in dendritic cells. maturation. (B) Following activation, DCs sustain high glycolytic rates to (A) Rapid induction of glycolysis in DCs by TLR stimulation serves an generate ATP to compensate for the loss of mitochondrial function. In anabolic role in DC activation, by generating lipids for synthesis of cDCs this process appears to be driven by autocrine type I interferon, additional membranes including ER and Golgi to support the increased while in inflammatory DCs this is a direct consequence of iNOS-derived demands of synthesis and transport of proteins required for DC NO that blocks OXPHOS. Frontiers in Immunology | Antigen Presenting Cell Biology May 2014 | Volume 5 | Article 203 | 2 Everts and Pearce Metabolic control of DC function studies illustrate that the induction of glycolysis plays a central DCs and cDCs in response to TLR stimulation (11, 13). More- role for DCs to acquire immunogenic properties as well as their over, consistent with its well-recognized role in regulating innate survival following activation. immune cell function under inflammatory conditions (42), TLR- While the metabolic features of immunogenic DCs are becom- induced DC activation and T cell priming appear to rely on HIF-1a ing more well characterized, there is still little known about the (11, 13, 43). However, whether this is a consequence of the role metabolism of tolerogenic DCs. Tolerogenic DCs, as opposed to of HIF-1a in promoting glycolytic metabolism and thereby cell immunogenic DCs, are generally characterized by the absence survival, or a reflection of the direct control of expression of of traditional signs of activation, are maturation-resistant, and inflammatory cytokines independently from glycolytic regulation express increased levels of immunoregulatory factors, impor- (44, 45), remains to be addressed. In addition to direct tran- tant for controlling Treg responses (19–21). Consistent with this scriptional regulation of glycolysis through HIF-1a, mTOR may immature, maturation-resistant phenotype, proteomic analysis of regulate the TLR-induced commitment to glycolysis indirectly in human DCs treated with dexamethasone and vitamin-D3, two inflammatory DCs, through induction of iNOS expression and well known immunosuppressive drugs that induce tolerogenic NO production (46, 47) that forces these cells to switch to glycolysis DCs, revealed increased expression of genes associated with mito- in the absence of mitochondrial respiration (12). chondrial metabolism and OXPHOS (22, 23). Furthermore, DCs In contrast to the clear role for the mTOR-HIF-1a axis in regu- conditioned by IL-4 acquire a phenotype highly reminiscent of lating TLR-induced long-term metabolic changes, recent evidence alternatively activated (M2) macrophages and expression of M2- suggests that the early TLR-driven induction of glycolysis to sup- associated activation markers on DCs is required for optimal port the anabolic demands of DC activation itself does not depend induction of IL-10-secreting T cells (24). The fact that M2 activa- on mTOR or HIF-1a signaling (16, 48). Instead, there is a critical tion by IL-4 is dependent on increased fatty acid oxidation (FAO) role for Akt in this response that directly enhances the enzymatic and OXPHOS (25–27) makes it conceivable that there is a causal activity of rate-limiting glycolytic enzyme hexokinase-II (HK-II) link between mitochondrial metabolism fueled by FAO and the by promoting its association with the mitochondria. Interestingly, acquisition of a tolerogenic phenotype by DCs. The observations Tank-Binding Kinase 1 (TBK1) and IkB kinase-(IKK) but not the that direct inhibition of glycolysis in TLR-activated DCs favors the canonical Akt activators PI3K or mTORC2 appear to be the cru- induction of Foxp3-expressing Th cells at the expense of IFN-g- cial upstream regulators of Akt activation in this TLR-driven rapid producing Th1 cells (16), and that resveratrol and rosiglitazone, induction of glycolysis (16). Taken together based on these recent drugs known to promote FAO (28) and mitochondrial biogen- findings a picture is emerging that TLR-signaling drives two func- esis (29), respectively, interfere with TLR-induced DC activation tionally and temporally distinct waves in glycolytic metabolism and can render them tolerogenic (30–33), would support this idea. in DCs that are controlled by largely separate signaling pathways However, these studies are mostly correlative and more work will (Figure 1). be needed to elucidate whether there is a direct functional link While the signaling pathways that promote the shift to glycoly- between mitochondrial catabolic metabolism and the acquisition sis and anabolic metabolism required for TLR-induced activation of tolerogenic properties of DCs. and immunogenicity of DCs are starting to be characterized, much less is known about the signals in DCs that may antag- REGULATORS OF DC METABOLISM onize these responses and that are potentially important for In recent years, major advances have been made in unraveling induction and function of tolerogenic DCs. In this respect, in the signaling pathways in immune cells that regulate their meta- T cells and in macrophages the metabolic sensor AMP Kinase bolic state. The conserved kinase mammalian/mechanistic target (AMPK) is known to play a central role in antagonizing biosyn- of rapamycin (mTOR) and its upstream activators PI3K-Akt have thetic pathways, including lipogenesis, and has instead been shown been identified as central regulators of cellular activation and pro- to promote catabolic metabolism by, amongst other pathways, the liferation due to their ability to control glycolysis and anabolic activation of peroxisome proliferator-activated receptor gamma metabolism (34–36). Consistent with a role for mTOR in regulat- coactivator (PGC)-1a that promotes mitochondrial biogenesis to ing DC metabolism as well, cDCs isolated from mice with a DC- increase mitochondrial OXPHOS (7, 35). Consistent with these specific deletion of tuberous sclerosis 1 (Tsc1), a negative regulator observations, pharmacological activation of AMPK suppresses of mTOR, display enhanced mTOR activity, an increase of expres- TLR-induced glucose consumption and activation of DCs, while sion of glycolytic and lipogenic genes, and of maturation markers knockdown of AMPK has the opposite effect (10, 49), suggesting at steady state (37). Also in response to TLR ligands inflamma- an important role for AMPK signaling in the metabolic con- tory DCs depend on signaling through PI3K, Akt, and mTOR for trol of DC activation. Furthermore, systemic administration of their long-term commitment to glycolysis (10, 38). mTOR pro- drugs activating AMPK signaling to promote catabolic metabo- motes anabolic pathways and glycolysis by driving expression and lism drives induction of tolerogenic immune responses in several stabilization of transcription factors such as sterol-regulatory ele- inflammatory disease models (50–52). However, it remains to be ment binding protein (SREBP) (39, 40) and hypoxia-inducible determined whether these treatments exert their effects through factor (HIF)-1a (41), that control expression of genes involved in direct induction of tolerogenic DCs. Moreover, resveratrol, a drug lipogenesis and glycolysis, respectively. While it remains unknown that has been linked to induction of tolerogenic DCs, is thought whether SREBP plays a role in DC metabolism, several studies have to favor catabolic metabolism through activation of the histone documented an important role for HIF-1a in supporting the long- deacetylase Sirtuin 1, which is known to suppress HIF-1a function term commitment in glycolytic metabolism of both inflammatory as well as enhance PGC-1a activity (29, 32, 53). In addition, www.frontiersin.org May 2014 | Volume 5 | Article 203 | 3 Everts and Pearce Metabolic control of DC function Based on the importance of anabolic metabolism and glycol- ysis in supporting DC activation and immunogenicity, and the possible role of catabolic metabolism in supporting tolerogenic DC function, it will be of great interest to assess whether promot- ing these types of metabolism in DCs can be used as a strategy to enhance the immunogenicity or tolerogenicity of DCs in therapeu- tic settings. It should be noted that some of the pharmacological approaches currently used to manipulate the immunogenicity of DCs, such as dexamethasone, Vitamin-D3, and rapamycin (63– 66) that are known for their capacity to induce tolerogenic DCs, have been described to influence DC metabolism (22, 23, 38). Thus it is possible that direct targeting of metabolism of DCs as a single treatment may not be superior to some other already existing manipulations that also affect metabolism. It is there- FIGURE 2 | Putative metabolic pathways and upstream regulators in tolerogenic versus immunogenic dendritic cells. In red examples are fore more conceivable that manipulation of metabolism of DCs depicted of pharmacological approaches currently tested or used in other for immunotherapy will be most effective when used in con- therapeutic settings, that could be used to manipulate DC metabolism. junction with existing approaches to complement and enhance their therapeutic efficacy. A second important advantage of direct enforcement of certain types of metabolism in DCs is that is DCs deficient for Nuclear factor-erythroid 2 p45-related factor- it may render them more resistant to environmental metabolic 2 (NRF2) or PPAR-g, downstream targets of PGC-1a, display manipulation. This is highly relevant since a key parameter that increased maturation and T cell priming capacity (31, 54, 55). determines the efficacy of immunotherapies is how long targeted Hence, these studies may point toward an important role for the DCs retain their phenotype following their functional manipu- AMPK-PGC-1a axis in promoting mitochondria-centered cata- lation. The microenvironment, which DCs become exposed to bolic metabolism in DCs, which may be crucial for the acquisition in situ, may lead to the loss of immunogenicity or tolerogenic- of a tolerogenic phenotype (Figure 2). However, how these signal- ity and would significantly affect the outcome of the therapy. For ing pathways are regulated under physiological conditions and to instance, the immunostimulatory capacity of DCs is often sup- what extent the effects of these factors on DC biology can be attrib- pressed in a tumor microenvironment (67). Given the important uted to direct regulation of DC metabolism are still unresolved role for cellular metabolism in regulating DC function, many of questions. the suppressive effects of tumors appear to be attributable to effects on DC metabolism. It has been shown that tumor-derived IL-10 MANIPULATING DC METABOLISM FOR THERAPEUTIC can suppress glycolysis in DCs through down regulation of gly- PURPOSES? colytic enzyme pyruvate kinase (68). Additionally, yet unidentified There is a great interest in the use of DCs as targets for immune- tumor-derived factors can promote aberrant lipid accumulation intervention and for vaccine strategies, because of their powerful in DCs, resulting in impaired T cell priming (69, 70). Moreover, immune stimulatory as well as regulatory functions (56). The immunogenic DCs are likely to be impaired in their function in use of highly immunogenic DCs can be used to promote robust a microenvironment where glucose will be scarce due to the high cellular and humoral immunity that is central for improving vacci- glycolytic rates of tumors themselves (71). Finally, caloric intake nation efficacy against a variety of infectious diseases and tumors, and mitochondrial activity are important determinants of organ- while the use of tolerogenic DCs will allow for induction of regula- ismal as well as cellular lifespan (72, 73). Therefore targeting DCs tory immune responses in settings where unwanted effector T cell metabolism can also be used to manipulate DC longevity to affect responses need to be controlled, such as to prevent rejection fol- their immunostimulatory potential. For example, mTOR inhibi- lowing transplantation. It is of pivotal importance to identify and tion has shown to increase the lifespan of TLR-activated DCs and characterize the regulatory processes underpinning these different enhance their capacity to induce protective tumor immunity (38). functions of DCs. It is becoming clear from the aforementioned Several agonist and antagonists of metabolic enzymes and studies that the activation and T cell-priming function of DCs is upstream signaling pathways that could be used to manipulate tightly regulated by their metabolic fate. What can we learn from DC metabolism have already been developed and tested for safety these new metabolic insights in DC biology and would there be and efficacy in other systems (58–60, 74) (Figure 2). In addition ways to use this knowledge in developing approaches to enhance to pharmacological approaches, genetic manipulation through DC-based immunotherapies? The idea of manipulating cellular introduction of small hairpin RNAs has shown to be a successful metabolism for therapeutic purposes is not a new concept. In fact, strategy to alter DC immunogenicity (75, 76) and could provide in the cancer field there is great interest in the use of pharmaco- a feasible alternative to target DC metabolism. In recent years, logicals that inhibit anabolic metabolism or glycolysis to reduce there has been a major focus on manipulating the immunos- tumor growth (57–60). Likewise, studies in T cells have provided timulatory properties ex vivo generated DCs for autologous DC a clear proof of principle that targeting of cellular metabolism can vaccination. Some of these vaccines have made it to the clinic (77) provide a viable means for improving the efficacy of vaccinations or are currently in clinical trials (78–80). In addition, widespread (61, 62). enthusiasm has been generated by results from the in vivo use of Frontiers in Immunology | Antigen Presenting Cell Biology May 2014 | Volume 5 | Article 203 | 4 Everts and Pearce Metabolic control of DC function nanoparticles, consisting of antibody covered micelles carrying 13. Pantel A, Teixeira A, Haddad E, Wood EG, Steinman RM, Longhi MP. Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for antigens and potentially drugs or shRNA, that can be specifi- maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol cally targeted to DCs in situ (81, 82). Given the amenability of (2014) 12(1):e1001759. doi:10.1371/journal.pbio.1001759 cellular metabolic intervention, it seems feasible that metabolism- 14. Dominguez PM, Ardavin C. Differentiation and function of mouse monocyte- targeted manipulations to DCs could be implemented in protocols derived dendritic cells in steady state and inflammation. Immunol Rev (2010) for DC-based vaccinations. 234(1):90–104. doi:10.1111/j.0105- 2896.2009.00876.x 15. Cleeter MW, Cooper JM, Darley-Usmar VM, Moncada S, Schapira AH. Reversible inhibition of cytochrome c oxidase, the terminal enzyme of the mito- CONCLUDING REMARKS chondrial respiratory chain, by nitric oxide. Implications for neurodegenerative It is becoming increasingly clear that the metabolic phenotype diseases. FEBS Lett (1994) 345(1):50–4. doi:10.1016/0014- 5793(94)00424- 2 of DCs dictates their activation and immunogenicity. However, 16. Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY, et al. TLR- driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon sup- many of the details and underlying mechanisms of how cellular ports the anabolic demands of dendritic cell activation. Nat Immunol (2014) metabolism controls the functional properties of DCs remain to 15(4):323–32. doi:10.1038/ni.2833 be determined. For instance, the precise metabolic processes that 17. Kidani Y, Elsaesser H, Hock MB, Vergnes L, Williams KJ, Argus JP, et al. Sterol reg- underpin the function of tolerogenic DCs are still poorly defined. ulatory element-binding proteins are essential for the metabolic programming Moreover, do different in vivo DC subsets have different meta- of effector T cells and adaptive immunity. Nat Immunol (2013) 14(5):489–99. doi:10.1038/ni.2570 bolic characteristics and are unique metabolic processes required 18. Ibrahim J, Nguyen AH, Rehman A, Ochi A, Jamal M, Graffeo CS, et al. Dendritic for DCs to perform particular functions, such as cross presenta- cell populations with different concentrations of lipid regulate tolerance and tion or the induction of Th1/2/17 cell responses? Addressing these immunity in mouse and human liver. Gastroenterology (2012) 143(4):1061–72. and other questions will not only contribute to a better funda- doi:10.1053/j.gastro.2012.06.003 19. Pulendran B, Tang H, Manicassamy S. Programming dendritic cells to induce mental understanding of the biology of DCs, but will also aid in T(H)2 and tolerogenic responses. Nat Immunol (2010) 11(8):647–55. doi:10. the rational design of metabolism-based approaches to enhance 1038/ni.1894 the efficacy of DC-based immunotherapies. 20. Svajger U, Obermajer N, Jeras M. Novel findings in drug-induced dendritic cell tolerogenicity. Int Rev Immunol (2010) 29(6):574–607. doi:10.3109/08830185. ACKNOWLEDGMENTS 2010.522280 21. Maldonado RA, von Andrian UH. How tolerogenic dendritic cells induce regula- The work was supported by the National Institutes of Health grants tory T cells. Adv Immunol (2010) 108:111–65. doi:10.1016/B978- 0- 12- 380995- to Edward J. Pearce (AI53825, CA164062), and by a Veni grant from 7.00004- 5 Netherlands Organisation for Scientific Research to Bart Everts. 22. Ferreira GB, Kleijwegt FS, Waelkens E, Lage K, Nikolic T, Hansen DA, et al. 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Cytother- Conflict of Interest Statement: The authors declare that the research was conducted apy (2013) 15(6):740–9. doi:10.1016/j.jcyt.2013.02.005 in the absence of any commercial or financial relationships that could be construed 77. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. as a potential conflict of interest. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med (2010) 363(5):411–22. doi:10.1056/NEJMoa1001294 78. Bregy A, Wong TM, Shah AH, Goldberg JM, Komotar RJ. Active immunotherapy Received: 01 February 2014; paper pending published: 02 April 2014; accepted: 24 April using dendritic cells in the treatment of glioblastoma multiforme. Cancer Treat 2014; published online: 08 May 2014. Rev (2013) 39(8):891–907. doi:10.1016/j.ctrv.2013.05.007 Citation: Everts B and Pearce EJ (2014) Metabolic control of dendritic cell activation 79. Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) and function: recent advances and clinical implications. Front. Immunol. 5:203. doi: study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Dia- 10.3389/fimmu.2014.00203 betes Care (2011) 34(9):2026–32. doi:10.2337/dc11- 0472 This article was submitted to Antigen Presenting Cell Biology, a section of the journal 80. Hilkens CM, Isaacs JD. Tolerogenic dendritic cell therapy for rheumatoid arthri- Frontiers in Immunology. tis: where are we now? Clin Exp Immunol (2013) 172(2):148–57. doi:10.1111/ Copyright © 2014 Everts and Pearce . This is an open-access article distributed under cei.12038 the terms of the Creative Commons Attribution License (CC BY). The use, distribution 81. Unger WW, van Beelen AJ, Bruijns SC, Joshi M, Fehres CM, van Bloois L, or reproduction in other forums is permitted, provided the original author(s) or licensor et al. Glycan-modified liposomes boost CD4+ and CD8+ T-cell responses by are credited and that the original publication in this journal is cited, in accordance with targeting DC-SIGN on dendritic cells. J Control Release (2012) 160(1):88–95. accepted academic practice. No use, distribution or reproduction is permitted which doi:10.1016/j.jconrel.2012.02.007 does not comply with these terms. www.frontiersin.org May 2014 | Volume 5 | Article 203 | 7

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